Head and neck squamous cell carcinoma (HNSCC) is the sixth most frequent cancer worldwide and despite optimized cytotoxic therapies, the 5-year survival rate of metastatic disease remains poor. Novel targets and therapies are clearly needed for disseminated disease. Receptor tyrosine kinases (RTKs) are attractive cancer targets due to: 1) frequent deregulation via mutation, amplification and/or autocrine/paracrine activation, 2) proximal positioning in oncogenic signal pathways and 3) specific targeting by small molecule tyrosine kinase inhibitors (TKIs) and inhibitory antibodies. To date, targeted therapies have not been effectively applied to HNSCC due, in part, to paucity of information on the dominant oncogene drivers. While the inhibitory EGFR antibody, cetuximab, is approved for use in HNSCC, overall effects are modest, likely due to failure to select for EGFR-addicted HNSCCs and/or rapid acquisition of resistance. While genomic approaches provide new information regarding tumor suppressors relevant to HNSCC, frequently mutated oncogene drivers were not generally identified. This observation raises the question of whether targeted therapeutics can, in fact, be successfully applied to this cancer. Our published findings identify a subset of HNSCC cell lines that is highly sensitive to FGFR inhibitors as well as a subset that is sensitive to EGFR-specific TKIs. In addition, our published and preliminary findings reveal putative roles for FGFRs in acquired resistance to EGFR-specific inhibitors. Together, these results support a hypothesis that an FGFR autocrine pathway is a dominant oncogene driver in a subset of HNSCCs. Moreover, specific FGFRs are candidates for acquired or intrinsic resistance mechanisms to EGFR inhibitors in HNSCC. To test these hypotheses, we will complete these Aims: Aim 1. Define the active FGFRs and FGFs that function as drivers in HNSCC cell lines and in primary HNSCC tumors directly propagated in nude mice. Also, the prevalence of FGFR pathway expression in archived HNSCC tumors will be defined. We will test the hypothesis that FGFR1 and specific FGFs and proteoglycan co-receptors are components of an oncogene driver pathway that functions in a clinically relevant fraction of head and neck tumors. Aim 2. Define FGFR-dependent and novel mechanisms of resistance to EGFR inhibitors in HNSCC. Our studies show rapid induction of FGFR2 and FGFR3 in EGFR- dependent HNSCC cells following treatment with EGFR-specific inhibitors as well as slower adaptive induction of FGFR1 and FGF2 during acquired resistance of EGFR-dependent HNSCC cell lines to gefitinib. We hypothesize that the failure of EGFR-targeted therapies to provide long-term control of HNSCC is due to multiple auxiliary growth pathways that reduce efficacy of EGFR inhibition alone. Completion of these specific aims is anticipated to unveil FGFR pathways as novel therapeutic targets in HNSCC. The ongoing early clinical development of multiple FGFR inhibitors could set the stage for their rapid application to this cancer that is highly relevant to the veteran population.